This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The aim of this project was to elucidate morphological changes in the organization of glutamatergic projections to the striatum of MPTP-treated parkinsonian monkeys. Two main series of experiments were completed during the past year. First, we used specific markers of the corticostriatal and thalamostriatal systems (vGluT1 and vGluT2, respectively) to assess changes in their pattern of synaptic connectivity and relative abundance in the striatum of MPTP-treated parkinsonian monkeys. Data obtained led to the following conclusions: (1) There is a significant increase in the density of cortical terminals in the striatum of parkinsonian monkeys, suggesting that changes in function of the corticostriatal system represent a key feature of Parkinson's disease pathophysiology in primates, (2) In contrast, the relative density of thalamostriatal boutons is not affected in MPTP-treated monkeys, but there was a significant change in their pattern of synaptic organization. To further understand morphological changes in striatal neurons that relate to the reorganization of the glutamatergic striatal afferents to the striatum in parkinsonian conditions, we analyzed changes in the density of spines on striatal projection neurons in MPTP-treated monkeys, and found a reduction of as much as 50% striatal spines after dopamine depletion. We also showed that the loss of spines was tightly linked to the level of striatal dopamine degeneration and that spines of both the "direct and indirect" striatofugal pathways are lost following dopamine depletion. Together, these findings provided strong evidence for the high level of plasticity and differential organization of the two main glutamatergic afferents to the primate striatum in normal and parkinsonian conditions.